Niacin (also known as nicotinic acid or vitamin B3) is an essential dietary constituent. Niacin deficiency leads to pellagra, which is characterised by loss of appetite, lethargy, weakness, diarrhea, dermatitis and mental changes.
There is evidence that niacin can treat dyslipidaemia as it reduces total cholesterol, low density lipoproteins (LDL, ‘bad’ cholesterol), and triglycerides, and increases high density lipoproteins (HDL, ‘good’ cholesterol). For example, when added to drugs for lowering cholesterol (statins), 2 g/day of slow-release niacin taken orally was more effective than ezetimibe (Zetia) in reducing carotid intima-media thickness, a marker of atherosclerosis. Additionally, clinical trials found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution.
Niacin is however associated with a high incidence of side effects including skin flushing, redness and burning. At therapeutic daily doses of 1.5-3 g/day, niacin often causes a painful skin flushing condition. Since the introduction of statins for lowering cholesterol, orally administered niacin has been avoided by clinicians as the side effects result in poor patient compliance. Moreover, as dyslipidaemia is an asymptomatic condition, patients are particularly less tolerant of medications causing side effects, such as niacin. Side effects with niacin administration have been a substantial limitation to its widespread use, and improvement in side effect control is required.
Immediate-release niacin is known in vitamin preparations. Extended-release niacin (Niaspan ER) has more recently become commercially available in the USA but has been associated with further problems of liver toxicity. Accordingly, there is a need for improved niacin formulations and methods of treatment which reduce the adverse side effects associated with its administration. EP 0643965 discusses administration of an oral dosage before periods of unconsciousness (eg sleep) but this has not proven to be commercially successful.
The prior art also discloses niacin compositions for oral administration and topical formulations containing niacin for transdermal delivery, see GB 1422768 and WO 2001/078727. Neither of these have been commercially successful.
Another problem facing clinicians is that the different statins now most commonly used to control cholesterol levels in patients have recently been found to be associated with serious side effects, including increased risk of diabetes and memory loss, that are not apparent to the patient. Clinicians are faced with an ever increasing demand for cholesterol control but increased concern over the safety of the standard family of drugs used to treat it.
The features of buccal administration of some drugs is known, with the distinctive property that absorption and delivery is very quick. Some cardiac medications are administered buccally so that immediate effects are achieved. Rapid absorption of niacin via this buccal route is undesirable as it may cause skin toxicity, so a means of slowing its absorption is desirable to reduce the adverse side-effects. The other characteristic of buccal administration is that drugs administered buccally generally avoid first-pass liver metabolism, which may be significant for dosing where the drug is liver-metabolised. Accordingly, buccal administration enables a reduction in the overall dose that is required to achieve a similar effect compared to oral administration.
Reference to any prior art in the specification is not, and should not be taken as an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.